The effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia.
Al Balushi, Halima
Rees, David C
Lu, David C-Y
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Al Balushi, H., Dufu, K., Rees, D. C., Brewin, J. N., Hannemann, A., Oksenberg, D., Lu, D. C., & et al. (2019). The effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia.. Physiological reports, 7 (6), e14027. https://doi.org/10.14814/phy2.14027
Sickle cell anaemia (SCA) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S (HbS) to increase oxygen (O2) affinity and reduce sickling. One of these, voxelotor (GBT440), is currently in advanced clinical trials. A structural analogue, GBT1118, was investigated in the current work. As RBC dehydration is important in pathogenesis of SCA, the effect of GBT1118 on RBC cation permeability was also studied. Activities of Psickle, the Gardos channel and the KCl cotransporter (KCC) were all reduced. Gardos channel and KCC activities were also inhibited in RBCs treated with Ca2+ ionophore or the thiol reagent N-ethylmaleimide, indicative of direct effects on these two transport systems. Consistent with its action on RBC membrane transporters, GBT1118 significantly increased RBC hydration. RBC haemolysis was reduced in a non-electrolyte lysis assay. Further to its direct effects on O2 affinity, GBT1118 was therefore found to RBC shrinkage and fragility. Findings reveal important effects of GBT1118 on protecting sickle cells and suggest that it may represent a powerful therapy for amelioration of the clinical complications of SCA.
Erythrocyte Membrane, Humans, Anemia, Sickle Cell, Hemolysis, Oxygen, Benzaldehydes, Niacinamide, Hemoglobin, Sickle, Symporters, Antisickling Agents, Cell Size, Permeability, Intermediate-Conductance Calcium-Activated Potassium Channels
Sultanate of Oman His Majesty Sultan Qaboos's 1000 grants British Heart Foundation
British Heart Foundation (PG/07/084/23286)
British Heart Foundation (PG/15/118/31966)
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External DOI: https://doi.org/10.14814/phy2.14027
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290099